MOLECULAR-PROPERTIES AND PHARMACOKINETIC BEHAVIOR OF CETIRIZINE, A ZWITTERIONIC H-1-RECEPTOR ANTAGONIST

The ionization and lipophilicity behavior of the antihistamine (H-1-re ceptor antagonist) cetirizine was investigated, showing the drug to ex ist almost exclusively as a zwitterion in the pH region 3.5-7.5. In th is pH range, its octanol/water lipophilicity is constant and low compa red to cationic antihistamines (log D = log P-Z 1.5), whereas its H-bo nding capacity is relatively large (Delta log P-Z greater than or equa l to 3.1). Conformational, electronic, and lipophilicity potential cal culations revealed that zwitterionic cetirizine experiences partial in tramolecular charge neutralization in folded conformers of lower polar ity. Pharmacokinetic investigations have shown the drug to be highly b ound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine d oes not differ from ''second-generation'' antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg(-1), smaller than that of exchangeable water) implies a low affinity for l ean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipo philicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of ''first-'' and ''second-generation'' drugs in th is class, could be considered as ''third-generation'' antihistamines.